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United States Patent |
5,139,025
|
Lewis
,   et al.
|
August 18, 1992
|
Method and apparatus for in vivo optical spectroscopic examination
Abstract
Methodology and apparatus for the clinical evaluation of biological matter,
in particular human anatomy, examined in situ and in vivo, by selective
spectral light transmissivity. An optical probe introduces selected light
spectra into the examination subject at a first position and resulting
light intensity at a second position located some distance from the
infusion point is measured; also, light reception preferably occurs at at
least one other location, and the effective distances between these
locations and the infusion point are determined. The light energy received
at the distant points is quantified and conditioned by use of the
effective distances from the infusion point and/or from one another, and
also by contrasting the data from the two differently-located reception
points, such that the resulting data quantitatively characterizes
intrinsic internal tissue characteristics in an absolute sense, devoid of
particular individual characteristics and variations such as skin
pigmentation, boundary composition or state, etc. The methodology is
especially characterized by the selection and use of particularly-located
first and second light-reception positions whose locations with respect to
the point at which the light spectra are introduced define particular
zones of interrogation and analysis, and whose location with respect to
one another may be comparatively examined (e.g., differenced) to
selectively define a particular internal volume whose structure or
conditional state is to be examined, quantified, and/or analyzed, all of
which is accomplished on a non-intrusive in vivo basis.
Inventors:
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Lewis; Gary D. (St. Clair Shores, MI);
Stoddart; Hugh F. (Groton, MA)
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Assignee:
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Somanetics Corporation (Troy, MI)
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Appl. No.:
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329945 |
Filed:
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March 29, 1989 |
Current U.S. Class: |
600/477; 600/475 |
Intern'l Class: |
A61B 005/00 |
Field of Search: |
128/632,633,653,665,664,666
250/358.1,339
356/432
|
References Cited
U.S. Patent Documents
Re31815 | Jan., 1985 | Alfano | 128/665.
|
4013067 | Mar., 1977 | Kresse et al. | 128/666.
|
4223680 | Sep., 1980 | Jobsis | 128/633.
|
4321930 | Apr., 1982 | Jobsis et al. | 128/633.
|
4515165 | May., 1985 | Carroll | 128/664.
|
4570638 | Feb., 1986 | Stoddart et al. | 128/665.
|
4649275 | Mar., 1987 | Nelson | 128/358.
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4655225 | Apr., 1987 | Dahne et al. | 128/664.
|
Other References
IBM Technical Disclosure Bulletin, vol. 10 No. 3, Aug. 1967 "Stacker
Selection System" by A. K. Brooks & C. J. Kellerman, pp. 225-226.
IBM Technical Disclosure Bulletin, vol. 10, No. 3, Aug. 1967 "MICR
Automatic Gain Control" by R. W. Arnold, pp. 227-228.
The Waters Company Advertisement, received in PTO Oct. 7, 1965 on X-350
Oximeter (Rochester, Minn.).
|
Primary Examiner: Pellegrino; Stephen C.
Assistant Examiner: Shumaker; Steven J.
Attorney, Agent or Firm: Price, Heneveld, Cooper, DeWitt & Litton
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of prior application Ser. No.
542,022, filed Oct. 14, 1983 (now U.S. Pat. No. 4,570,638) and is also
related to prior U.S. Pat. applications Ser. Nos. 827,526 and 830,578 (now
U.S. Pat. No. 4,817,623), the disclosures of which are incorporated herein
by reference as fully as though set out in total.
Claims
The embodiments of the invention in which an exclusive property or
privilege is claimed are defined as follows:
1. A method of non-obtrusively and non-invasively examining the conditional
state of physiological substance located within a particular internal
volume inside a test subject by optical response, comprising the steps:
introducing light of selected wavelengths into said subject from a source
location on the outside periphery of said subject; selecting at least
first and second light-detection locations on said subject at points
spaced from one another and spaced from said source by unequal first and
second distances such that a first mean optical path is established
extending through a portion of said subject disposed between said source
and said first detection location and a second mean optical path of a
different length is established extending through a different portion of
said subject disposed between the source and said second detection
location, said second optical path extending through said particular
internal volume while said first optical path generally lies within a
different internal volume located nearer said source location than and
said particular internal volume; detecting the intensity of light of said
selected wavelengths at said first and second detection locations
resulting from said introduction of light at said source location; and
differentially comparing the said light intensities detected at said first
and second detection locations to thereby obtain examination data which
particularly characterizes said particular internal volume without effects
attributable to said different internal volume.
2. The method of claim 1, wherein said step of differentially comparing
comprises subtraction of optical response data obtained by detecting said
light intensity at said second location from optical response data
obtained by detecting said intensity at said first location.
3. The method of claim 1, wherein said physiological substance comprises a
highly scattering and partially absorptive media and said light
wavelengths, source location and detection locations are selected such
that said mean optical paths comprise generally spherical curves.
4. The method of claim 3, wherein said step of differentially comparing
comprises subtraction of optical response data obtained by detecting said
light intensity at said second location from optical response data
obtained by detecting said intensity at said first location.
5. The method of claim 1, including the step of selecting a test subject
which comprises a body extremity having internal tissue of a nature
different than its external periphery, and wherein said light is selected
and introduced in a manner such that said second optical path traverses
said internal tissue at a depth well beyond said external periphery while
said first optical path length lies primarily within said external
periphery.
6. The method of claim 5, wherein said step of differentially comparing
comprises subtraction of optical response data obtained by detecting said
light intensity at said second location from optical response data
obtained by detecting said intensity at said first location.
7. The method of claim 1, wherein said test subject comprises the head of
an animate being and said light is introduced and detected such that said
second path is sufficiently long to traverse the brain tissue while said
first path is sufficiently short to traverse primarily only the scalp and
skull.
8. The method of claim 7, wherein said step of differentially comparing
comprises subtraction of optical response data obtained by detecting said
light intensity at said second location from optical response data
obtained by detecting said intensity at said first location.
9. The method of claim 7, wherein said light is introduced and detected in
a manner such that said second optical path is selected to have a length
which traverses a predetermined internal brain area.
10. A method of appraising the internal structure of selected organic
bodies and materials wherein light energy is used as an investigative
media by transmissing it through said bodies and materials and producing
quantitative data from such light which characterizes the composition,
condition and/or physiology of a particular area of said internal
structure, comprising the steps of:
placing optical source and receiver probe members in optically-coupled
relation with the selected body or material and sending light of selected
wavelengths from said source probe member into the selected body or
material to transmiss the same;
receiving the resulting light from said body or material at separate and
mutually-spaced first and second locations, said first location being near
that at which said selected light is sent into said body or material from
said source in relation to said second position;
quantifying the resulting light which is received at said first location as
well as quantifying the resulting light received at said second location
to obtain optical response data values; and
using said data values for resulting light received at said first location
to condition the said data values for resulting light received at said
second location by modifying one such set of quantified data values as a
function of the other, to thereby remove from the resulting conditioned
light-response data values optical effects resulting from factors
attributable to impingement of the light upon and passage thereof through
the outer perimeter of the selected body or material, whereby quantified
optical response data valuations are obtained which characterize the
internal structure of a particular area within said body or material on a
generally intrinsic basis and which are substantially independent of
perimetral characteristics.
11. A method of quantitatively characterizing internal organic structure
according to claim 10, in which said different wavelength-related data
value representations for said first and second locations are combined by
comparatively differencing them.
12. A method of quantitatively characterizing internal organic structure
according to claim 11, in which said step of receiving resulting light at
a first location disposed relatively near that at which said light is sent
into said body or material from said source is carried out by using a
detector which is carried with said source and disposed at a measured
distance from the location of light emission therefrom.
13. A method of quantitatively characterizing internal organic structure
according to any of claims 10, 11 or 12, in which said step of receiving
resulting light at said first location includes receiving such light at a
point located not more than about five centimeters from the place at which
said selected light is introduced into said selected body or material.
14. A method of quantitatively characterizing internal organic structure
according to any of claims 10, 11, or 12, which includes the steps of:
establishing a measure of the nominal optical distance between said first
and second locations of light reception while said probe members are held
in said optically-coupled relation; and
conditioning the quantified wavelength-related optical response data values
by modifying them in accordance with the particular nominal optical
distance between said probe members whose measure has been determined with
said probe members fixed in said optically-coupled relation, to thereby
produce numeric optical response data which quantitatively characterizes
the internal structure of said body or material on a wavelength-related
basis which is substantially independent of the distance between said
first and second receivers, and which is thus directly comparable with
other such quantitative and conditioned data obtained from other and
different organic bodies or materials.
15. A method of quantitatively characterizing internal organic structure
according to any of claims 10, 11 or 12, which includes the further steps
of:
preparing composite averages of said quantified and conditioned
wavelength-related data values from a plurality of different individual
organic bodies or materials; and
using said composite averages as a basis for comparison with the quantified
and conditioned data values obtained from a particular individual organic
body or material.
16. A method of quantitatively characterizing internal organic structure
according to claims 11 or 12, which includes the steps of:
moving said optical probe members from said first and second locations to
other pairs of locations on the same such body or material;
holding said optical probe members in optically-coupled relation with such
body or material at such other locations; and
repeating said steps of sending selected light wavelengths, receiving
resulting light, quantifying and conditioning received light data values
by modifying the data values for one of the locations in a pair as a
function of the data values for the other such location in that pair, to
thereby condition the light-reception data for such other locations and
thus provide meaningful mutual comparison with other such quantified and
conditioned data regardless of the particular location at which it was
obtained.
17. A method of quantitatively characterizing internal organic structure
according to claim 16, which includes the further steps of preparing
composite averages of said quantified and conditioned wavelength-related
data values from a plurality of different individual organic bodies or
materials, classifying said composite averages as a function of their
corresponding investigative wavelength, and using such classified
composite averages as a basis for comparison with the particular
quantified and conditioned data values obtained from a specific individual
organic body or material.
18. Apparatus for obtaining optical response data from organic bodies which
is representative of the internal nature of tissue within such bodies,
including:
at least one optical probe member including a source and at least two
receivers adapted for placement in operational proximity with selected
areas on said body and adapted to pass light of selected wavelengths from
said source to said receiver through such body;
means for holding said source and receivers in predetermined relation while
in their said positions of operational proximity to the selected areas of
the said body;
said receivers including means for receiving the resulting light which has
passed through said body at a first position with respect to said light
source as well as means for receiving such light at a second position
located further away from said source than said first position, and for
producing corresponding quantified data values for each such position
which are correlated with said selected wavelengths; and
means for modifying the said quantified data values for light received at
one such position as a difference function of the corresponding data
values for light received at the other such position in a manner such that
the resulting quantified and modified data values are representative of
intrinsic interior characteristics of said body and generally free of
optical effects resulting from factors attributable to impingement of the
light upon and passage thereof through the outer perimeter of said body
and in a manner such that said resulting data values are primarily
representative of the conditional state of a particular internal tissue
volume whose location within said body is predetermined by the particular
location and disposition of said first and second positions relative one
another;
said first light-receiving means carried with said optical probe member at
a position within not more than about ten centimeters from the location of
said light source, for receiving certain of said light projected by said
source into said body following scatter effects upon said light occurring
within said body at a location relatively close to said source, and said
second receiving means being positioned further from said light source and
within about thirty centimeters from the location of said light source.
19. Optical response apparatus according to claim 21, wherein said first
receiving means is carried with said optical probe member at a position
closely adjacent said light source.
20. Apparatus according to claim 18, wherein said light source and at least
a first one of said receivers is carried by a common optical probe member.
21. Apparatus according to claim 20, wherein said common probe member
further carries a second optical receiver.
22. Apparatus according to claim 21, wherein said probe member comprises a
single probe unit in which said source and said first and second receivers
are mounted.
23. Apparatus according to claim 22, wherein said first and second
receivers are mounted in said probe member in fixed position.
Description
TECHNICAL FIELD
This invention relates generally to optical spectrophotometric examination
and/or analysis of tissue and/or other biological materials or substances,
especially human tissue or other such biological substance, i.e., use of
spectrally-selective optical (light) propagation and response technology
for such examination and/or analysis purposes; more particularly, the
invention relates to methodology and apparatus involving the use of
optical spectrophotometric technology on an in vivo basis in human
subjects for analytic and diagnostic purposes. Still more particularly,
and in some of its more specific attributes, the invention relates to
certain novel applications and methodology in examination of, and the
production and presentation of clinical physiological data with respect
to, human anatomy by use of optical response observations, e.g., light
transmissivity response measurements and characterization; in particular
involving the use and relative positioning of two or more receivers for
the light spectra introduced into the examination subject and detected
after undergoing reflection, scatter and absorption effects within the
subject, by which a particular internal volume may be selectively examined
spectrophotometrically.
BACKGROUND OF THE INVENTION
In academia, and particularly in biological and medical research
activities, among practically innumerable studies, experiments and
laboratory examinations, a relatively small but frequently recurring
interest has been shown in the use of light, in various different forms,
as an investigative and/or diagnostic tool or instrumentality. A
relatively primitive emanation of this interest is evidenced in the
various forms of transillumination which have been experimented with and
used in many different ways over a great many years, probably dating back
into antiquity, and in general utilizing light relatively crudely, i.e.,
as a visual aid, to help produce visually-perceptible shadows, shapes and
images within or upon what would otherwise be substantially opaque objects
or surfaces. In other more complex procedures, light energy of
particularly-selected parameters is impinged upon or injected into the
subject matter to be investigated and interpreted from the standpoint of
the quantity or nature of the light detectable at another location,
typically opposite the point of injection. This approach frequently
includes the use of spectrometers at the point of detection, and may or
may not involve the use of particularly-selected wavelengths of light for
application to the subject under study.
Thus, in earlier efforts utilizing basic transillumination, a typical
approach would be to utilize a source of visible light coupled by a
tubular shield or the like to a translucent body portion or object which
is then viewed carefully from the opposite side with the human eye, often
aided by various reflectors, magnifiers and the like. One
immediately-available example of such a procedure is that utilized by
physicians for examination of human sinus conditions. An example of the
more complex type of procedure would be a scientific study such as for
example is illustrated in scholarly publications of the type entitled
"Infrared Microspectrum of Living Muscle Cells," by Darwin L. Wood
(Science, Vol. 1, Jul. 13, 1951), in which different particular individual
types of muscle fibers were placed between transparent plates and placed
in the radiation beam of a microspectrometer, where they were subjected to
various wavelengths of light up to about ten microns, with the detected
transmission intensities being plotted according to wavelength. With
respect to the efforts to use transillumination generally, further
reference is made to publications such as that by M. Cutler, M.D., in the
Jun., 1929, issue of Surgery, Gynecology and Obstetrics, entitled
"Transillumination As An Aid In The Diagnosis Of Breast Lesions," and as
to the more complex spectrophotometric procedures, reference is made to an
article in the Aug. 5, 1949, issue of Science (Vol. 110), by Blout and
Mellors, entitled "Infrared Spectra Of Tissues."
While the aforementioned article by Cutler discussed basic
transillumination procedures for diagnosis of breast disease as early as
1929, a number of proposals for refinement and enhancement of the basic
transillumination procedures have been suggested in intervening years.
Thus, the use of color film was proposed in 1972 by Gros and Hummel, and
Ohlsson et al. proposed in 1980 the use of infrared film rather than
ordinary color film, both using visible yellow light as well as infrared
or rear infrared light as the illumination. Carlson has further proposed
the use of a Vidicon system as a detector or collector, but the ultimate
analysis and interpretation is nonetheless done visibly
In the area of spectrophotometric analytic and diagnosis efforts, infrared
oximeters have been developed and utilized in relatively recent years for
non-invasive monitoring of the oxygenation of blood in humans and other
specimens, most typically by contact with the ear or finger extremity, a
selected infrared wavelength being coupled to the involved body portion
with detection occurring on the opposite side of such portion, variations
in the light energy detected being directly indicative, after appropriate
calibration, of the oxygen content of the blood flowing through the
affected body portion, as a result of the known absorption references of
particular infrared wavelengths by oxygenated hemoglobin. Somewhat
analogous observations and/or phenomena may be discerned by contemplation
of publications such as those by Blout and Mellors, noted above, which
noted a dramatic increase in the intensity of light as the 9.3 micron band
in cancerous breast tissue as compared to normal breast tissue and the
proposed explanation that the 9.3 micron band is also one of the strong
intensity bands for the enzyme ribonucleaes, which rapidly increases in
amount in rapidly proliferating cancer cells.
Various publications of Frans Jobsis commencing in about 1977 and including
U.S. Pat. Nos. 4,223,680, 4,281,645, 4,321,930 and 4,380,240 are based
upon a somewhat analogous although specifically different reported
phenomena, i.e., the spectrally distinctive absorption characteristics
associated with the cellular enzyme cytachrome a, a.sub.3, which in turn
is said to be integrally associated with, and indicative of, oxydative
metabolism. On this basis, Jobsis proposed the use of a
particularly-selected measuring wavelength and another carefully selected
reference wavelength to produce apparent differences in detection level,
which differences were said to demonstrate, and actually be indicative of,
organ vitality or viability, since indicative of oxydative metabolism and
therefore of oxygen sufficiency, the premise being that the chain of
causation between the observed measurements and the body organ believed to
be under investigation, i.e., internally subjected to the injected light,
was complete and inclusive.
GENERALIZED DESCRIPTION OF THE INVENTION
In a broad and underlying sense, the present invention rests upon a basic
foundation of optical spectrophotometry as used in connection with
physiologic conditions and principles as generally described in the
above-referenced related applications, involving the effects of light
transmissivity (scatter and absorption) within the tissue under
observation. That is, from one standpoint, the invention is broadly based
upon the principle that light, and especially selected wavelengths of
light (generally within the band of from 0.6 micron to 1.5 micron, by way
of example) are transmissible through at least portions of the human body
in varying degrees as a significant and characteristic function of
particularizing scatter and absorption effects of the specific tissue
under examination.
Thus, it has been found in accordance with one aspect of the invention that
a given body portion will, when suffused with a selected group of
wavelengths, exhibit a definitive and repeatable optical response, which
may be used to characterize and demonstrate a particular physiological
condition and composition and, it is believed, to show abnormality or
anomaly, particularly when compared to other such responses taken from the
same individual (i.e., person) both at other points in time and/or from
other and complementary or analogous body portions (e.g., the opposite
breast), as well as when compared to readings or profiles, and/or
composites thereof, taken from the same body portions of other humans,
especially related groupings of particular humans.
Further, the invention provides methodology and apparatus for obtaining
optical response data indicative of intrinsic tissue characteristics and
independent of individual and ethnic factors such as color, degree of
pigmentation, age, skin thickness, etc., which is uniquely useful in the
above-noted type of approach, as well as in other and more general
clinical ways.
More particularly, the invention provides methods and apparatus for
obtaining spectral transmissibility data for clinical study and analysis,
particularly of human anatomy viewed in vivo, to provide a further
clinical instrumentality for the study of such anatomy, hopefully to help
bring about better understanding of its physiology, particularly with
respect to its current status, and also with respect to effects caused by
anomaly, abnormality, disease, injury, trauma and/or other adverse
conditions and states.
In a broad sense, the invention is directed to a new method and apparatus
for obtaining optical response data by examining biological tissue in
vivo, yielding highly useful information as to the intrinsic composition,
condition and physiology of an internal volume of tissue whose location
and size depends upon the relative positioning and location of optical
probes.
In a more particular sense, the invention contemplates the injection of
light (and particularly sequential bursts of particularly-selected light
wavelengths, or narrow bands) into the selected body part at a given
location, and the detection of the amount of resulting light which emerges
and is detected, or received, at least two locations, one typically
disposed nearer the point of injection and one or more others, typically
located relatively farther from the injection point.
Generally speaking, the two such detection locations are chosen to satisfy
two conditions; i.e., the injected light must have similarly passed into
and out of the skin at each different location, and the light must have
sampled (propagated through) at least partially different areas and
amounts of internal tissue. By comparative analysis of the resulting light
reception data, effects related to impingement and entry (as well as
exiting) of the light through the skin and a given adjacent area are
cancelled out, and the resulting data thus pertains to and in effect
samples the tissue within a specifically selected internal volume or
region. Since the relative geometrical locations and spacing of the light
receivers are known and the nominal optical distance, and particularly the
difference between the optical distance between the location of the near
receptor, or receiver, and that of the far receptor or receiver, is
determined in accordance with the invention, these are used as
conditioning factors in quantifying the resulting light-reception data.
Thus, such data is directly and meaningfully appropriate for use in
comparative studies of, and for averaging and compositing with respect to,
different individuals regardless of whether they are of the same or
different racial, ethnic or pigmentation characteristics, and regardless
of particular physical differences and the like, from one subject to
another.
Accordingly, the present invention provides methodology and apparatus which
are especially characterized by the selection and use of
particularly-located first and second light-reception positions whose
locations with respect to the point at which the light spectra are
introduced define particular zones of interrogation and analysis, and
whose location with respect to one another may be comparatively examined
(e.g., differenced) to selectively define a particular internal volume
whose structure or conditional state is to be examined, quantified, and/or
analyzed, all of which is accomplished on a non-intrusive in vivo basis.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a pictorial illustration showing an overall system in accordance
with previous and incorporated U.S. Pat. No. 4,570,638, which also
illustrates the general environment and apparatus in accordance with the
present invention;
FIG. 2 is an enlarged, side elevational view of an optical probe generally
in accordance with Applicants' co-pending and incorporated application
Ser. No. 827,526, which further illustrates apparatus useful in
understanding the present invention;
FIG. 3 is an end view of another example of an optical probe useful in
practicing the present invention;
FIG. 4 is a side elevational view of the probe shown in FIG. 3;
FIG. 5 is a pictorial, schematic illustration showing a first arrangement
of light source and light-detection receivers helpful in understanding the
present invention;
FIG. 6 is a second pictorial, schematic illustration showing a second
arrangement of light source and light-detection receivers helpful in
understanding the present invention;
FIG. 7 is a pictorial, schematic illustration somewhat similar to FIGS. 5
and 6 but showing further aspects of optical probe geometry in accordance
with the present invention;
FIG. 8 is a further view similar to that of FIG. 7 but showing other
aspects of probe geometry; and
FIG. 9 is a further view similar to that of FIGS. 7 and 8, but showing
further aspects of probe geometry.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The general nature and general usage of one form of apparatus in accordance
with the invention is illustrated pictorially in FIG. 1, which is
reproduced from Applicants' earlier U.S. Pat. No. 4,570,638, incorporated
herein by reference. Stated in the most basic terms, optical measurements
or readings are taken by use of a manually-manipulatable test instrument
10 which is coupled by cables 12 and 14 to a control unit 16 which
includes an input keyboard 18 for actuation and control purposes, a CRT
visual display 20 on which data may be displayed in various formats, and a
housing 22 in the form of a cabinet which encloses associated light
sources, electrical supply apparatus, data-handling electronics and
data-processing apparatus including for example a microcomputer (which may
be a small digital device of the type known as a "personal computer,"
e.g., the IBM "P.C." or generally similar device), together with
interconnected data storage (e.g., floppy disk drive) and a digital
printer or plotter of a conventional nature.
With continuing reference to the apparatus shown in FIG. 1, it will be
observed that the test instrument 10 includes a first side or portion 24,
referred to hereinafter as a "component member," as well as a second such
portion or "component member" 26, both of which are, in this particular
embodiment, disposed in mutually-aligned opposition. This mutual alignment
(geometry), selected for this particular application, is maintained by
support means comprising, in this example, fixed and movable carriers 27,
27', respectively, mounted upon a rigid interconnecting alignment and
positioning bar 28 which carries length-measurement indicia 29.
While many different particular structures or mechanisms may be utilized
for the basic purpose of maintaining a given desired geometric
relationship, i.e., "alignment," of the "component members" while
permitting desired relative movement, one relative basic arrangement for
axial relationships of the type illustrated in FIG. 1 is that of a
modified dial caliper. A more refined version of such a device is shown in
FIG. 2 and fully described in Applicants' related and co-pending
application Ser. No. 827,526, filed Feb. 10, 1986, which is also
incorporated by reference herein.
The significance of the nominal optical distance information readable from
the indicia on the bar 28 or otherwise provided by the test instrument 10
will be explained more fully hereinafter, but it should be noted that the
availability and utilization of such information is decidedly important to
the invention. Thus, whatever spacial relationship or geometry is desired
for the light source and receivers in a given embodiment, the support
means utilized must be arranged to provide the effective or nominal
optical distances involved, whether the component members are fixed or
movable. In the embodiment illustrated in FIG. 1, this information is
entered into the computer via the keyboard 18 by the operator, but it may
be preferred to utilize a form of the test instrument 10' such as that
shown in FIG. 2 and described in co-pending application Ser. No. 827,526,
having a transducer which automatically provides this information as a
coordinated part of the overall procedure.
As may further be seen in FIG. 1, the test instrument 10 utilized for that
procedure places the two component members 24 and 26 on opposite sides of
the breast or other such body extremity which is to be examined. In the
case of the human female breast, several different readings are preferably
taken, for purposes discussed more fully in the referenced and
incorporated related cases, and in that procedure the orientation of the
test instrument, and of the two component members, is preferably generally
vertical in taking each such measurement or reading. This results from the
particular interstructure of the breast, however, which is much more
symmetrical from one vertical section to the next. Thus, in the
breast-examination procedure of the referenced co-pending cases, the
instrument is moved from place-to-place by manual manipulation, and in
each instance the two component members are moved apart to the extent
necessary, placed over the breast in the desired positioning, and then
gently moved toward one another to the extent necessary to provide full
contact between the inner surface of each component member and the breast,
so as to preclude the entry or exit of any light from between the breast
and each of the component members.
The structural nature of component member 24 is disclosed in detail in
related and referenced U.S. Pat. No. 4,570,638 and a more refined and
improved version thereof is disclosed in co-pending application Ser. No.
827,526. Generally speaking, this member includes a cylindrical outer
shell or cover, which may be a thin metal or polymeric member, and houses
an optical emitter (e.g., a fiber optic terminal coupled to a source of
selected light spectra) and one or more optical detectors. The detectors
may be a light guide fitted to a fiber optic cable which exits the
component member with the light source fiber optic, collectively
constituting the aforementioned cable 12. In the embodiment illustrated in
FIG. 1 and described in detail in Applicants' prior U.S. Pat. No.
4,570,638, the detectors in component member 24 are disposed along a
circular arc which is centered upon the optical fiber constituting the
light-emitting source, and the distance (radius) between such optical
fiber cable and the receivers should, in that embodiment, preferably be in
the range of about one to three centimeters, preferably not more than
about two centimeters. As will be seen below, this distance is an
important factor, and is selected to accomplish particular purposes, since
the detector associated with member 24 constitutes a "near" receiver which
receives light energy which has been introduced ("injected") by the
optical fiber bundle into the particular body portion or extremity with
respect to which clinical data is desired to be obtained, but which has
traversed a shorter path, having entered that body portion and merely
encountered reflection and "backscatter" from the internal tissue located
directly beneath the skin rather than deep within the subject.
Thus, the light energy detected by the "near" detectors has passed through
the skin of the subject and through the adjacent internal tissue of the
breast (or other body portion) but has immediately exited by passing back
outward through the skin, at a point relatively near the source. This
"near" detection signal is very important in accordance with the
invention, as will be explained more fully hereinafter, and should not
include light which has merely passed directly from the end of the fiber
optic into the detectors without ever having passed into and out of the
skin and adjacent tissue of the subject. In the particular embodiment
illustrated in prior Pat. No. 4,570,638, the light energy detected at the
"near" position represents light reflected generally toward the source,
which has not traversed substantial distances within the breast tissue and
emerged far away from the source; however, in accordance with the broader
aspects of the disclosure in this prior patent, and with the more
particular discussion set forth hereinafter, the "near" receivers may be
selectively positioned so that the apparatus "samples" a particular area
or zone in the test subject constituting a selected tissue volume or
location.
The "far" receiver component 26 for the embodiment of prior Pat. No.
4,570,638, illustrated in FIG. 1, is similar in basic structure to
component 24 discussed above, including an outer shell through which an
electrical cable 14 enters and exits. Component 26 does not include a
light source, however, and instead houses a desired array of light
detectors (i.e., one or more detectors), mounted in a predetermined
location. As noted in prior Pat. No. 4,570,638, and as described fully
below, the "far" receiver may be located much closer to the source and
"near" receiver than is the case in the apparatus shown in FIG. 1 since
the particular location selected for the far receiver is coordinated with
that selected for the "near" receiver, such that the apparatus "samples" a
particular area or zone in the test subject constituting a selected tissue
volume or location.
It should be understood that terms used herein such as "direct" or
"transmitted" and "reflected" are adopted primarily for purposes of
convenience and illustration, and not to indicate that there are
fundamental differences between the light energy that emerges at any given
point from the selected body portion after injection. Actually, it is
believed that all injected light undergoes multiple and diverse scatter
effects throughout its tortuous path of propagation within the body
portion in which it has been injected. Thus, the present invention
contemplates use of the overall optical response provided by comparative
analysis of the "near" and "far" detection signals, which response is
viewed as complex in nature and quite conceivably involving molecular
(Rayleigh) scattering, particle (Mie) scattering, index (Fresnel and
Christiansen Effect) scattering, fluorescence (especially infrared
fluorescence), inelastic (Raman) scattering, and both spectral and
non-spectral energy absorption. Thus, the circumstances and the
methodology are considerably more complex than simple in vitro laboratory
spectrophotometry, and the responses obtained in accordance herewith may
well depend upon such factors as molecular structure, the types and size
distributors of the cells, the amount, nature and distribution of fat
cells, and of connective tissue, the blood supply and vascularization
metabolism, the lymph system, and glandular activity.
As indicated previously in conjunction with the discussion of FIG. 1, the
component members 24 and 26 are, in that particular embodiment, held in
direct alignment with one another by the carriers 27, 27' and the bar 28.
More particularly, in this arrangement the alignment is such that the
light-injecting fiber optic or other such source component is
substantially aligned along the same axis with at least one of the "far"
detectors. This arrangement is not at all necessarily utilized, however,
as pointed out more fully below.
To a substantial degree, a primary aim of the present invention is to
obtain clinical, physiological data for selected body portions, and
particularly of selected tissue location, by optical response methodology.
More particularly, the clinical data obtained in accordance with the
present invention represents intrinsic, internal tissue properties
particular to a selected location within the test subject.
In accomplishing the objectives of the invention, the above-noted means for
determining the particular distance between the component members of the
optical probe (i.e., the "nominal optical distance") involved in a given
measurement or scan is of considerable importance, as is the determination
and appropriate usage of both "far" light propagation data and "near"
data. With respect to the second such point, a significant feature of the
present invention is the realization that "near" transmissibility data
should be obtained and in effect used as a measure of the light energy
actually injected into the interior of the body portion under examination,
after the effects of impingement upon and passage through the skin and
immediately adjacent tissue, etc. This "near" detection level is
subtracted from the "far" detection data, since by so doing one may
compare the amount of light energy which has passed completely through, or
at least traversed a substantial portion of, the body portion under
examination with the amount of light energy which has only transmissed a
lesser volume of internal tissue, and thus remove from consideration the
many data-modifying characteristics arising from individual differences of
skin, bone, etc., as well as all such characteristics representative of a
tissue volume adjacent to the particular volume desired to be selectively
examined.
Furthermore, the knowledge and appropriate utilization of the particular
nominal optical distance involved in each different optical scan over
whatever different wavelength spectra have been selected and over whatever
different body portion or path has been selected is also of great
significance, since this optical distance is utilized in accordance with
the invention to condition the data obtained and thus remove the otherwise
inherent variation of light energy propagation as a function of optical
distance or thickness. In this connection, it should be clearly understood
that the particular arrangement illustrated in FIG. 1, with axial
alignment of the receivers and close positioning of the "near" detector to
the light source, is not at all the only effective such arrangement. That
is, while at least one "near" and one "far" detector are required, they
need not be positioned on a straight-line basis if some other (e.g.,
relative angular positioning with respect to the light source) arrangement
is desired, as for example to better accommodate a particular anatomical
area to be studied. In any such arrangement, the effective or nominal
optical paths involved for the particular positions of the receivers must
be determined, since such distances characterize the different tissue
volumes sampled by the different receivers. That is, proximity of the near
detector to the point of light injection may be "built into" the scale
which is read to determine the optical distance for the "far" detector,
and where both locations are fixed the corresponding distances will of
course be predetermined and may be used directly, without measuring or
reading out. In any case, utilization of the measured or
otherwise-determined effective or resultant optical distance, by which the
mean optical path length may be determined or closely approximated, is
accomplished y using it as the "thickness" or length parameter in
application of the exponential relationship attributed to Beers and known
as Beers' Law, to develop intrinsic light propagation magnitude values for
the internal tissue of the selected body portion.
While it is not the purpose of this disclosure to focus upon any particular
methodology and/or apparatus for actually making this data compensation or
specifically implementing the data-conditioning principles, it may be
noted that data-handling procedures of this general nature are readily and
indeed routinely obtained through use of known techniques and routines in
the use of digital computers, and that appropriate results may also be
obtained directly through electrical signal-processing approaches, in
hardware (circuitry), since discrete digital components such as adders,
subtracters and digital dividers are of course in widespread use and
widely diverse availability. It is the general underlying principle and
methodology of such approaches which is here involved, i.e., arrival at
intrinsic-type data by conditioning the signal values actually received
from the "far" receivers through use of the "near" receiver data, together
with use of the nominal optical distance measurement determined for each
particular measurement set, as discussed below.
As indicated previously above, the particular location selected for the
"near" and "far" receivers or detectors symbolized by first component
member 24 and second component member 26 in FIG. 1 (and by the comparable
members 24', 24" and 26', 26" of FIGS. 2, 3 and 4) provides the capability
of selecting a particular volumetric sample within the test subject whose
characteristics may be non-invasively examined and quantitatively
determined in accordance with the present invention. Thus, where the
"near" and "far" receivers are positioned in the manner illustrated in
FIG. 1, the tissue volume which is examined is somewhat like that
pictorially illustrated in FIG. 5, wherein a hypothetical in vivo body
extremity or portion 30 (e.g., the human breast, generally in accordance
with Applicants' prior Pat. No. 4,570,638, or other such body extremity
capable of being transmissed by selected light spectra) is illustrated
with the light source portion 24a (providing a source "S" of selected
light spectra) located at the twelve o'clock position, the "near" receiver
24blocated at approximately the one o'clock position, and the "far"
receiver 26a located at the six o'clock position. In this arrangement,
essentially the entire internal volume of the test subject 30 is sampled
by subtracting the output O.sub.1 received at the near receiver 24b from
the output O.sub.2 received at the far receiver position.
As noted in prior Pat. No. 4,570,638, however, the near and far receivers
do not have to be disposed in the particular locations, or at the relative
spacing, depicted in FIGS. 1 and 5, and may be positioned in other
locations so that other and different particular tissue volumes will be
examined, in a selective manner. Thus, the optical probes illustrated in
FIGS. 2 and 3 show other dispositions of near and far receivers, which may
be used for this purpose in accordance with the "near-far" subtractive
processing methodology noted above and described mathematically herebelow.
The optical probe 10' shown in FIG. 2 is much like that described in detail
in Applicants' co-pending application Ser. No. 827,526; however, whereas
that particular application shows an optical probe whose two component
members have relatively fixed or "hard-mounted" positions, the component
members 24' and 26' in the probe 10' shown in FIG. 2 include means for
changing the relative orientation and positioning of the "near" and "far"
1 . receivers, e.g., a manually-operable telescoping slide joint 32, 34 by
which the two such component members may be moved further inboard or
outboard from the main support portion of the probe. Furthermore, the
probe 10' of FIG. 2 includes rotatable couplings 36, 38 for the component
members 24' and 26', respectively, by which such members may be rotated
with respect to one another and with respect to their corresponding
support members. Both such position-changable mechanisms should permit
easy position adjustments by hand, and preferably are position-retaining,
or at least lockable in selected positions by threaded collars or
thumbscrews. Both such mechanisms may be generally of a conventional
nature and utilize known mechanisms such as friction-lock slide members,
spring-loaded ratchet-type or other such detents, etc.
As disclosed in co-pending application Ser. No. 827,526, referred to above,
an internal transducer such as a potentiometer may be utilized to
automatically provide an output signal which directly measures the mutual
separation of the two component members 24' and 26'. In the same manner,
such a transducer may be utilized to automatically indicate the relative
changes in position brought about by use of the manually-manipulatable
joints 32, 34 and the couplings 36, 38. Accordingly, the component members
24' and 26' of the probe 10' shown in FIG. 2 may be utilized by
manipulating the two component members so as to fit any given geometry in
the test subject, and thereby to sample a particular selected internal
volume thereof, generally as illustrated in FIGS. 5 and 6, and in so doing
the aforementioned transducers will provide outputs automatically
determinative of the particular spacial positioning of the two probes
relative one another. The three degrees of relative movement described
above are generally sufficient to conform to most in vivo test subjects;
of course, a further such degree of freedom could be provided by a rotary
coupling disposed in a plane generally orthogonal to that of the supports
for the component members 24' and 26', such that the two may be disposed
along axes positioned at an acute angle with respect to one another.
The probe 10" illustrated in FIGS. 3 and 4 is a further example of a
somewhat simplified version of an instrument generally characterizing the
foregoing discussion but having the positions of the source and both the
near and far receivers fixed in a predetermined relative location (in this
regard, it is to be noted that the particular position of the source with
respect to the near receiver may also be changed, and varied, generally in
accordance with the variable probes discussed above). Thus, as illustrated
in FIGS. 3 and 4, the probe 10" includes a source 24a, a near receiver
24b, and a far receiver 26a, all of which are mounted in the same support
structure (here, a cylindrical housing 110 having an end wall 112) at
relative positions which are particularly selected to sample a specific
and predetermined tissue volume within a particular test subject, for
example comparable to that depicted in FIG. 6 (i.e., the arcuately-sided
somewhat cone-like volume whose transverse section is designated by the
numeral 40 in FIG. 6). In this arrangement, the source 24a and near
receiver 24b may be considered the "first component member" 24" and the
far receiver 26b considered the "second component member," i.e., the first
and second component members constituting opposite halves of the probe
10".
In point of fact, a probe 10" such as that illustrated in FIGS. 3 and 4 may
be specifically designed with the relative locations of the source 24a the
near receiver 24b, and the far receiver 26a, all selected so that the
configuration samples a very particular physiological area or volume, in
which particular physiologic structure exists, for example, a particular
volume within the head located beneath the scalp and skull, which may be
selected to include only a small number of brain gyra. At the same time,
the location of the "near" receiver may be chosen so that it primarily
samples only the skin and selected adjacent matter (e.g., in a probe
configured for the head, only or primarily the scalp and skull), so that
these effects may be removed from the resulting data when the "near"
detector output is subtracted from the "far" detector output. In such a
probe designed for the top portion of the human head (which has very
little musculature) the elements are located as indicated in FIG. 3 and
separated by a distance of about eight mm. between the source 24a and the
near receiver 24b, and a distance of about twenty-five mm. between the
common transverse axis of the source 24a and near receiver 24b, on the one
hand, and the far receiver 26a on the other. For simplicity, the source
24a and receivers 24b, 26a are shown in this FIG. as simply being a fiber
optic 14" terminating flush with a polymeric support grommet 48, the
source fiber optic leading back to a light source and the receiver fiber
optics leading back to electro-optical detectors. Other configurations are
shown in the above-identified, referenced and incorporated applications.
The sketches shown in FIGS. 5 and 6 constitute simplified illustrations of
the mean distribution of optical paths (referred to hereinafter as the
mean optical path) for light travelling from source point S to a receiver
point 0 (designating output) in a medium having much higher scattering
characteristics than absorption, such as is essentially the case in the in
vivo tissue examination constituting the subject matter of Applicants'
prior and present patent applications. In such a case, the shape of the
mean optical path is spherical (or in any event partially spherical)
(which is intended to be illustrated in all of FIGS. 5, 6, 7, 8 and 9). In
FIG. 7, this spherical mean optical path is designated by the curved loci
42, 42', and 42", which have a center C located at the mid-point of a line
extending through points S and 0. In the idealized case illustrated in
FIG. 7, where light enters and leaves through a planar surface of a
homogenous medium of the type referred to, the sampled volume between
points S and 0 is thus hemispherical.
The spectral attenuation of light under conditions such as those referred
to above, and shown pictorially in FIG. 7, is affected by the absorption
characteristics of the media being transmissed and the optical path
length. The absorption characteristics are thus a function of the
particular absorptivities (.alpha.) of specific molecular bonds,
multiplied by the concentrations (.gamma.) of these molecules. The
attenuation due to absorption by a specific molecular bond in such a
medium is thus described as:
##EQU1##
where: I = output intensity
I.sub.1 = input intensity
.alpha. = absorptivity of the molecular bond
.gamma. = concentration of the molecular bond in the optical field
l - optical path length
The primary underlying principle of optical absorption spectroscopy such as
that referred to herein and in the referenced and incorporated prior
patent and applications may be considered to be the proposition that
relative concentrations of molecular bonds may be determined from the
known or determined quantities referred to in the preceding paragraph, in
which the quantity (is related to the aforementioned mean path length by
the expression:
l = C.sub.sc .multidot.l.sup.1
in which:
l.sup.1 = length of the mean path
C.sub.sc = scatter factor, from multiple scattering events
As indicated above, in many applications or instances the examining light
spectra must not only travel through a particular boundary material or
structure (such as skin, bone, etc.) which is different than the
particular tissue or substance composition within the organ or body part
desired to be examined, but in addition there may be a particular area
further within such organ or body part whose particular attributes are to
be examined, and it is desirable to do so without having the data
influenced by the characteristics of adjacent generally similar tissue
(e.g., as generally illustrated in FIG. 6). Such a situation is more
particularly illustrated in FIG. 8, which generally depicts a model for
light travelling through two distinguishable media, or in any event media
locations, designated 44 and 46, respectively, volume one constituting in
effect a layer of thickness "t." Thus, in FIG. 8 the examining light
spectra originally originated at source S, with an intensity I.sub.i,
passes through layer 44, and then transmisses tissue volume 46 along a
mean path 42', which may be considered semicircular in shape, from a
virtual source S' to a virtual output point O', from where it passes
directly back outward through layer 44 to an actual output point O.
With further reference to FIG. 8, the length of the mean optical path 42'
is given by the expression:
l.sub..mu. =.pi. .multidot.C.sub.sc.mu. .multidot.t
in which the layer or region 44 comprises a medium having characteristics
described or determined by the factor ".mu.."
Considering that area 46 comprises a different medium having
characteristics ".epsilon.," the light passing through virtual source S'
traverses a path whose length is characterized by mean path 42", which
path length is given by the expression:
l.sub.68 =.pi..multidot.C.sub.sc.epsilon. .multidot.[O'-S']
Of course, the incident light must also pass back out through layer 44 in
order to be detected at point O (as intensity I.sub.o). Thus, a further
calculation, or repetition, of the expression set forth above for
calculating l is required.
Accordingly, the overall attenuation of the incident light I.sub.i in
traversing layers 44 and 46 and ultimately being detected at point O, as
intensity I.sub.o, may be determined as follows:
##EQU2##
Accordingly, in a two-sensor system of the type illustrated generally in
FIG. 6, the relationship is that indicated in FIG. 9, in which the actual
and virtual sources S, S' are depicted in the manner discussed in
connection with FIG. 8, but in which a first "near" receiver is disposed
at a first output point O.sub.a, at which a light intensity I.sub.a is
detected, and a second (far) receiver is located at an output point
O.sub.b, where a light intensity I.sub.b is detected. In accordance with
the discussion set forth above, it will be appreciated that by use of such
a system the effects of light transmittal through medium ".mu." may be
removed from the resulting optical response data actually used to assess
the state or condition of the internal tissue volume desired to be
examined
That is, as stated above, the separation between the source S and the
location of the "near" receiver (O.sub.A in FIG. 9) may be used to control
the depth of the mean optical path therebetween (designated 142 in FIG.
9), which may thus be made to correspond to mean path 42', extending
between actual source S and virtual source S'. Of course, mean path 42'
actually does traverse the entire thickness of medium 44' (of
characteristics .mu.), while mean path 142 is of the same path length but
extends laterally through layer 44' rather than transversely across it.
Accordingly, the output at O.sub.A, comprising intensity I.sub.A, will
characterize the layer 44' (which, in the case of cranial examination,
will characterize the scalp and skull). As already indicated, by use of
the subtractive processing in accordance with the invention, the resulting
data will characterize only the tissue transmissed along mean path 42",
i.e., will be devoted exclusively to revealing the characteristics of
medium .gamma..
That is, with reference to the equations set forth previously, and assuming
that the dimension "t" is known (actually determined empirically or
approximated in accordance with known information), and assuming further
that the scatter factors C.sub.sc.mu. and C.sub.sc.gamma. are
approximately equal (designate C.sub.sc below for convenience), the light
intensity ratio characteristic of mean path 42" (the "deep" tissue), plus
that attributable to mean path 42' extending through layer 44', is given
by the expression:
##EQU3##
The analogous intensity ratio relative to only the layer 44' (the
"shallow" mean path) is given by the expression:
##EQU4##
By converting to logarithmic form for convenience, the subtraction of the
second expression just set forth above from the first such expression is
readily accomplished; therefore, the light intensity data characteristic
of only mean path 42" (i.e., the "deep" data which characterizes only
medium 46', of characteristics ".epsilon.") is given by the expression:
##EQU5##
Accordingly, it will be seen that by careful selection of the relative
positions of the "near" and "far" receivers, in relation to the source,
and by practice of the subtractive data conditioning contemplated by the
present invention, selected internal tissue volumes may be examined on a
non-invasive basis without "contamination" by the characteristics of other
adjacent tissue or body structure.
The quantified and conditioned data provided through the practice of the
present invention, may advantageously be displayed in a number of ways,
e.g., by tables of magnitudes and by various forms of plots and graphical
presentations utilizing the compensated and weighted magnitudes, whether
specifically portrayed in relation to wavelengths or otherwise, not only
by means of separate graphical presentations for each different location
from which data is obtained, but also by taking complementary scans of
complementary body portions. For example, in the case of breast
examination, by taking a set of measurements for both breasts with similar
relative positioning of the hand instrument 10, i.e., both left and right
breasts along the inner (central) marginal edges, along the outer marginal
edges, centrally near the chest wall, and centrally outward away from the
chest wall. The resulting data provided in accordance with the invention
may also be presented in the form of color maps, by use of known
color-mapping programs commercially available for digital computers of the
type referred to herein. For example, the data obtained for particular
wavelength groupings may be assigned different colors, and the colors
overprinted within a map area as a function of received signal intensity
after conditioning as described hereinabove. This will yield yet another
form of data presentation which will have widely-differing color content
and distribution, according to the characteristics of the tissue sampled,
which will have different evaluative effects for different persons which
may be preferred by some. Regardless of which particular form of data
presentation is selected, the formatted data may then be meaningfully
compared to similarly formatted data for the same patient, and the records
so obtained preserved for comparison with similar records taken at other
points in time. Further, such results may be comparatively examined with
respect to other results obtained from other particular individuals, both
those who may be known to be "normal" (i.e., not known at that time to
possess specific and identified abnormality or disease), as well as for
those who may have diagnosed abnormality or illness.
It is believed self-evident that consideration of the results obtained in
accordance herewith and as discussed in the related and referenced
applications and patent identified above demonstrates not only the
presence of meaningful data but also the potential of a highly useful
methodology. In this respect it is not the purpose of this specification
to assert a complete, comprehensive and finalized description and
explanation of all of the very complex physical and chemical factors
involved in the propagation of light through living tissue, nor for every
meaningful aspect of the data obtained by the method and apparatus
disclosed; further, it is not intended to teach complete and definitive
methodology for specific medical diagnosis. Instead, it is intended to
show highly useful methods and apparatus for clinical examination and
study of human subjects, and for presentation of the data so achieved,
including comparative presentations for similar positions on different but
analogous body portions of the same patient, and for a broad cross section
of different patients at both the same and different ages, and also with
respect to particular patients at various different points in their
lifespan. Thus, while the invention contemplates the presence of
clinically efficacious modalities which may be useful for many purposes
perhaps including diagnosis of particular conditions and/or illness, it is
presently contemplated that perhaps the most useful contribution of the
invention is to provide a screening device and modality in which a
familiar and therefore non-frightening medium (i.e., "light") is utilized
in a harmless and non-invasive procedure made possible by relatively
inexpensive apparatus operable by medical technicians as opposed to
physicians themselves, primarily useful for indicating the need (or lack
thereof) for much more intensive analytical investigation, i.e.,
mammography, ultrasound, biopsy, etc.
It should be noted that the instant application and the related and
referenced cases disclose concepts and methodologies principally described
as applicable to study of the human female breast, but which are not at
all limited to use for this purpose That is, optical response and
particularly spectral response data obtained in the manner described
herein is definitely considered to be appropriate for, and valuable in,
examination of other body portions, human or otherwise. While it may or
may not be true that a given such application may call for slightly
varying the specifics of the modality in actual application, the basic
underlying concepts should nonetheless prove applicable and effective.
Accordingly, the scope of this patent should be determined by
consideration of the appended claims rather than with respect to specific
attributes or parameters set forth above and/or in the attached drawings,
describing and illustrating various preferred embodiments or
characteristics, the scope of the claims to be determined through
appropriate application of established principles of patent law including
the doctrine of equivalents.
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